An activator protein known as ectodysplasin isoform A1, (EDA-A1, hereinafter referred to as EDA1) is required for normal development of several ectodermally-derived organs in humans and mice. This influence on normal development is executed through the action of EDA1 binding to its receptor EDAR.
The ectodysplasin gene (EDA) codes for 2 protein splice isoforms, EDA1 and EDA2, which differ by the absence of Val207 and Glu308 in EDA2, a difference sufficient to specify binding and activation of two different receptors, EDA1 receptor (EDAR) and X-linked EDA1 receptor (XEDAR), respectively as detailed in “The anhidrotic ectodermal dysplasia gene (EDA) undergoes alternative splicing and encodes ectodysplasin-A with deletion mutations in collagenous repeats” Bayés M et al. Hum Mol Genet. 1998 October; 7(11):1661-9 and “Two-amino acid molecular switch in an epithelial morphogen that regulates binding to two distinct receptors” Yan M et al. Science. 2000 Oct. 20; 290(5491):523-7 the contents of which are incorporated herein by reference in their entireties.
The discovery and descriptions of EDA2 include those described in detail in U.S. Pat. No. 5,700,926 filed Jul. 22, 1996 which is a continuation of U.S. Pat. No. 5,556,786 filed Apr. 27, 1993, the contents of which are incorporated herein by reference in their entireties. The discovery and descriptions of XEDAR include PCT application PCT/US2000/009699 now granted patents EP1169448B1 filed May 8, 2013, U.S. Pat. No. 6,534,061 filed Apr. 12, 2000, and U.S. Pat. No. 7,198,913 filed Sep. 12, 2002 the contents of which are incorporated herein by reference in their entireties. Additionally, descriptions of multimeric TNF receptors are included in international application PCT/EP2009/057396 filed Jun. 15, 2009.
The EDA1 receptor is referred to as EDAR and the EDA2 receptor is referred to as XEDAR. EDA1 and EDA2 belong to the tumor necrosis factor (TNF) family as classified by the expression of a TNF homology domain. The TNF homology domain of EDA1 (from Gln247 to Ser391) and EDA2 (from Gln247 to Ser389) is more conserved than that of any other TNF family members, with human EDA being 100% and 98% identical to mouse and chicken EDA, respectively.
EDAR and XEDAR regulate aspects of ectodermal development by activation of NF-κB signaling pathways. The EDA1-EDAR axis plays a predominant role in the development of skin-derived structures, including hair and sebaceous glands. EDA2 and XEDAR are less well defined, but may play a role in myodegeneration, hypohidrotic dysplasia, and androgenic alopecia. XEDAR is closely related to the orphan receptor TROY. Based on a careful sequence analysis of EDA, EDAR, XEDAR, and TROY in various species, it has been hypothesized that TROY might be the receptor for EDA2 in vertebrates, with the exception of marsupials and mammals, where the specificity of EDA2 would have shifted to XEDAR.
Efforts to treat developmental diseases have focused on improvement of the interaction between EDA1 and EDAR. One of these approaches is the use of recombinant proteins containing the receptor-binding domain of EDA1 fused to the C-terminus of an IgG1 Fc domain. The publication “Permanent correction of an inherited ectodermal dysplasia with recombinant EDA”, O. Gaide et al., Nature Med., 2003, 9(5), 614-618, describes the administration of recombinant EDA1 to developing embryos and newborn Tabby mice in order to correct the phenotype and provide a basis for a possible treatment of XLHED.
Such an approach is also described in US Patent 2005152872 (Gaide et al.), which is incorporated herein by reference in entirety. In particular this document discloses a recombinant fusion protein containing an amino-acid sequence which comprises: (a) the Fc section or part of an Fc section of an immunoglobulin as component (A) or a functional variant of component (A); (b) the extracellular part of a TNF ligand or a partial sequence of the extracellular part of a TNF ligand as component (B) or a functional variant of component (B); and optionally (c) a transition area between component (A) and component (B), containing a linker.
PCT publication number WO2010113117, which is incorporated herein by reference in entirety, describes agonist anti-EDAR antibodies as another approach for treating developmental disorders. The process of improving the action of EDAR by providing agonists is used to counteract the poor interactions between EDA1 and EDAR that lead to developmental disorders.
In contrast to the developmental disorders arising from poor interactions between EDA1 and EDAR, a number of other disorders of varying severity are postulated to arise from excessive action of EDA1. Such conditions include hirsutism (excessive hair growth), ectopic teeth and/or excessive growth of teeth, hyperhidrosis (excessive sweating), sebaceous gland hyperplasia, breast cancer, dermal eccrine cylindroma, and skin conditions arising from overactive sebaceous glands, such as sebaceous gland hyperplasia, comedones, milia, acne, seborrhea, rosacea, steatoma, or furuncles.
There is a need to provide treatments for conditions arising from excessive action of EDA1. There is also a need to provide assays for quantitation of EDA1 and which facilitate characterization of pharmacokinetic and/or pharmacodynamic profiles of individuals being treated with recombinant EDA1 for developmental disorders arising from a lack of action of EDA1. The present invention addresses these needs.